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Developing Diagnostic Tests for Fanconi Anemia and Unraveling the Genetics of the Disease

Fanconi anemia is a rare, recessively inherited blood disorder. The outward signs of the disease vary widely-in addition to low counts of red and white blood cells and platelets, some people with Fanconi anemia are born with birth defects. In childhood or as teenagers people with Fanconi anemia commonly develop aplastic anemia, acute myelogenous leukemia, or other forms of cancer. In 1981 Rockefeller geneticist Arleen Auerbach (1937- ) developed a blood test for definitively diagnosing this disorder, and she went on to demonstrate that test could be modified for prenatal diagnosis using cells from amniotic fluid or chorionic villi.

Auerbach, Arleen

In the 1960s researchers had observed an increased rate of chromosomal breakage in cells cultured from Fanconi anemia (FA) patients. The diagnostic test pioneered by Auerbach-known as the DEB test, and still the standard test today-takes advantage of this fact. She found a great increase in the frequency of chromosome breakage when blood lymphocytes from people with FA were treated with dose of diepoxybutane (DEB), a DNA cross-linking agent, which had no effect on cells from healthy individuals.

The introduction of bone marrow transplantation provided the means to cure FA, but identifying tissue type-matched donors who are able and willing to donate their bone marrow (or circulating stem cells) is challenging. The Auerbach laboratory's work on the prenatal diagnosis of Fanconi anemia led them and colleagues elsewhere to investigate the use of a newborn's umbilical cord blood instead. Like bone marrow, cord blood contains stem cells that develop into normal blood cells. The first human cord blood transplant was in a Fanconi patient in 1988. Thus, Fanconi anemia became a model for the development of umbilical cord blood transplantation as an alternative to bone marrow transplantation in the treatment of hematologic disorders more generally. The success of hematopoietic stem cell transplant using cord blood from tissue-matched healthy sibling donors conceived as "savior siblings" led to Fanconi anemia becoming the model for genetic testing and the selection of embryos based on their suitability as a tissue donor. The combination of conception by in vitro fertilization (IVF) and pre-implantation genetic diagnosis (PGD) enables selection of disease-free embryos that are a good tissue match for transfer to a woman's womb to initiate a pregnancy.

Auerbach also has been a leader in identifying the genes responsible for FA. In 1996 the Auerbach laboratory and others in a consortium identified the gene that is most commonly defective in Fanconi anemia. Known as FANCA, it accounts for up to 65 percent of FA cases. With this information, molecular genetic tests could be developed to identify carriers of the disease-people with only one copy of the gene, who do not have the disease but can pass a defective gene to their children. Auerbach and her colleagues also have played a major role in identifying the FA genes FANCJ/BRIP1, FANCN/PALB2, and FANCI. Advances in Fanconi genetics by Auerbach and others have been aided by the International Fanconi Anemia Registry, which Auerbach established at the Rockefeller Hospital in 1982. The registry, which contains tissue samples and cell lines from more than 600 FA patients, is an essential resource for the study of the clinical and genetic features of FA. Thirteen genes are now known to underlie the various manifestations of the disease, and more are likely to be discovered.

Arleen D. Auerbach received the BA from William Smith College (1957), the MA from Columbia University 1958), and the PhD from New York University (1977). She did postdoctoral work in the Laboratory of Cancer Genetics and Cytogenetics at Memorial Sloan-Kettering Cancer Center before joining Rockefeller in 1982, as assistant professor in the Laboratory for Investigative Dermatology. She also held adjunct positions at North Shore University Hospital and Weill Cornell Medical College. She began the Human Genetics and Hematology laboratory in 1995. Auerbach is an elected fellow of the American Association for the Advancement of Science (2006). She held a MERIT award from the National Heart, Lung and blood Institute from 1997-2007.

Selected Publications

Auerbach AD, Warburton D, Bloom AD, and Chaganti RSK. Prenatal detection of the Fanconi anemia gene by cytogenetic methods. Am J Hum Genet, 1979, 31: 77-81

Auerbach AD, Adler B, and Chaganti RSK. Prenatal and postnatal diagnosis and carrier detection of Fanconi anemia by a cytogenetic method. Pediatrics, 1981, 67: 128-135

Auerbach AD, Sagi M, and Adler B. Fanconi anemia: prenatal diagnosis in 30 fetuses at risk. Pediatrics, 1985, 76: 794-800
http://pediatrics.aappublications.org/cgi/content/abstract/76/5/794

Auerbach AD, Zhang M, Ghosh R, Pergament E, Verlinsky Y, Nicolas H, and Boue J. Clastogen-induced chromosomal breakage as a marker for first trimester prenatal diagnosis of Fanconi anemia. Human Genet, 1986, 73: 86-88

Auerbach AD, Rogatko A, and Schroeder-Kurth TM. International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood, 1989, 73: 391-396

Auerbach AD. Fanconi anemia diagnosis and the diepoxibutane (DEB) test. Exp Hematol, 1993, 21: 731-736

Gluckman E, Broxmeyer HE, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P, Copper S, English D, Kurtzberg J, Bard J, and Boyse EA. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med, 1989, 321: 1174-1178

Auerbach AD. Umbilical cord blood transplants for genetic disease: Diagnostic and ethical issues in fetal studies. Blood Cells, 1994, 20: 303-309

Bielorai B, Hughes MR, Auerbach AD, Nagler A, Loewenthal R, Rechavi G, and Toren A. Successful umbilical cord blood transplantation for Fanconi anemia using preimplantation genetic diagnosis for HLA-matched donor. Am J Hematol, 2004, 77: 397-399

Apostolou et al. Positional cloning of the Fanconi anaemia group A gene. Nature Genet, 1996, 14: 324-328

Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P, Batish SD, Kalb R, Velleuer E, Barral S, Ott J, Petrini J, Schindler D, Hanenberg H, and Auerbach AD. The BRCA1 interacting helicase BACH1/BRIP1 is deficient in Fanconi anemia. Nat Genet, 2005, 37: 931-933

Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, Wurm M, Batish SD, Lach FP, Yetgin S, Neitzel H, Ariffin H, Tischkowitz M, Mathew CG, Auerbach AD, and Rahman N. Biallelic mutations in PALB2, which encodes a BRCA2 interacting protein, cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet, 2007, 39: 162-164

Sims AE, Spiteri E, Sims III RJ , Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Kalb R, Schindler D, Hanenberg H, Auerbach AD, and Huang TT. Identification of FANCI, a functional homolog of FANCD2 that regulates the Fanconi anemia pathway. Nat Struct Molec Biol, 2007, 14: 564-567

Links

Arleen Auerbach, Laboratory of Human Genetics and Hematology
http://www.rockefeller.edu/labheads/auerbach/index.php

Gene Identified For Most Common Form of Fanconi Anemia
http://www.scienceblog.com/community/older/1996/A/199600413.html

Hospital Centennial

Developing Diagnostic Tests for Fanconi Anemia and Unraveling the Genetics of the Disease

Selected Publications

Further Reading

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